[go: up one dir, main page]

US6433004B1 - Substituted β,γ-anellated lactones - Google Patents

Substituted β,γ-anellated lactones Download PDF

Info

Publication number
US6433004B1
US6433004B1 US09/600,430 US60043000A US6433004B1 US 6433004 B1 US6433004 B1 US 6433004B1 US 60043000 A US60043000 A US 60043000A US 6433004 B1 US6433004 B1 US 6433004B1
Authority
US
United States
Prior art keywords
compound
general formula
formula
alkenyl
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US09/600,430
Other languages
English (en)
Inventor
Andreas Stolle
Horst-Peter Antonicek
Stephen Lensky
Arnd Voerste
Thomas Müller
Jörg Baumgarten
Karsten Von Dem Bruch
Gerhard Müller
Udo Stropp
Ervin Horváth
Jean-Marie-Viktor De Vry
Rudy Schreiber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Assigned to BAYER AKTIENGESELLSCHAFT reassignment BAYER AKTIENGESELLSCHAFT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STOLLE, ANDREAS, VON DEM BRUCH, KARSTEN, MULLER, GERHARD, STROPP, UDO, DE VRY, JEAN-MARIE-VIKTOR, HORVATH, ERVIN, SCHREIBER, RUDY, VOERSTE, ARND, LENSKY, STEPHEN, MULLER, THOMAS, ANTONICEK, HORST-PETER, BAUMGARTEN, JORG
Application granted granted Critical
Publication of US6433004B1 publication Critical patent/US6433004B1/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to ⁇ , ⁇ -fused lactones, to processes for their preparation and to their use as pharmaceuticals.
  • the amino acid L-glutamate is the most important excitatory neurotransmitter in the brain. Glutamate receptors can be divided into into two major classes: 1. ionotropic receptors which control the ion channels directly and 2. metabotropic receptors (mGluRs).
  • ionotropic receptors which control the ion channels directly
  • mGluRs metabotropic receptors
  • Metabotropic glutamate receptors are a heterogeneous class of G-protein-coupled receptors. Pre- and postsynaptically, they modulate the release of glutamate and the sensitivity of the cell to glutamate, respectively. The effects are caused via different second-messenger cascades. This response, in turn, has an effect on the ionotropic glutamate receptors.
  • the present invention relates to ⁇ , ⁇ -fused lactones of the general formula (I)
  • R 1 and R 2 together represent radicals of the formulae
  • R 3 represents hydrogen, (C 1 -C 6 )-alkyl or represents (C 2 -C 6 )-alkenyl
  • R 4 represents a radical of the formula —CH 2 —R 5 ,
  • R 5 represents aryl having 6 to 10 carbon atoms or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to polysubstituted by identical or different substituents from the group consisting of halogen and (C 1 -C 6 )-alkyl,
  • R 3 represents (C 2 -C 6 )-alkenyl
  • R 4 represents hydrogen
  • the compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers).
  • the invention relates both to the enantiomers or diastereomers and their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform components in a known manner.
  • Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particular preference is given, for example, to salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiusopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines, such as, for example, diethylamine, triethylamine, ethyldiusopropylamine, procaine, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine or
  • aryl represents an aromatic radical having 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • (C 1 -C 6 )-alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • (C 2 -C 6 )-alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 3 to 5 carbon atoms. Examples which may be mentioned are: vinyl, allyl, isopropenyl, but-3-en-1-yl, n-pent-3-en-1-yl and n-hex-3-en-1-yl.
  • R 1 and R 2 together represent radicals of the formulae
  • R 3 represents hydrogen or represents (C 2 -C 5 )-alkenyl
  • R 4 represents a radical of the formula ⁇ CH 2 —R 5 ,
  • R 5 represents phenyl, naphthyl or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to polysubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and (C 1 -C 4 )-alkyl,
  • R 3 represents (C 2 -C 5 )-alkenyl
  • R 4 represents hydrogen
  • R 1 and R 2 together represent radicals of the formulae
  • R 3 represents hydrogen or represents (C 3 -C 5 )-alkenyl
  • R 4 represents a radical of the formula ⁇ CH 2 —R 5 ,
  • R 5 represents phenyl, naphthyl or benzothiophene which is attached via the heterocycle, where the ring systems are optionally mono- to disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and (C 1 -C 3 )-alkyl,
  • R 3 represents (C 3 -C 5 )-alkenyl
  • R 4 represents hydrogen
  • R 1 and R 2 are as defined above.
  • R 4 is as defined above
  • A represents halogen, preferably bromine
  • R 1 , R 2 and R 4 are as defined above,
  • R 3′ has the meaning of R 3 given above. but does not represent hydrogen.
  • D represents halogen, preferably bromine
  • R 2 and R 3′ are as defined above,
  • Suitable solvents are all inert solvents which do not change under the reaction conditions. These preferably include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether. Particular preference is given to tetrahydrofuran.
  • Suitable bases are the customary inorganic or organic bases. These preferably include alkali metal hydroxides, such as, for example, sodium hydroxide, potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or amides, such as sodium amide, lithium bis-(trimethylsilyl)amide, lithium diisopropylamide, or organometallic compounds, such as butyllithium or phenyllithium. Preference is given to lithium diisopropylamide and lithium bis-(trimethylsilyl)amide.
  • alkali metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide, or alkali metal carbonates, such as sodium carbonate or potassium carbonate, or sodium methoxide or potassium methoxide, or sodium ethoxide or potassium ethoxide or potassium tert-but
  • the base is employed in an amount of from 1 to 5, preferably from 1 to 2, mol, based on 1 mol of the compounds of the general formulae (III) and (IV).
  • the reaction is generally carried out in a temperature range of from ⁇ 78° C. to reflux temperature, preferably from ⁇ 78° C. to +20° C.
  • the reaction can be carried out under atmospheric, elevated or under reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
  • the compounds of the general formula (I) according to the invention are suitable for use as medicaments in the treatment of humans and animals.
  • the compounds of the general formula (I) according to the invention are suitable for modulating metabotropic glutamate receptors and therefore influence the glutamatergic neurotransmitter system.
  • a modulator of the metabotropic glutamate receptor is an agonist or antagonist of this receptor.
  • the compounds according to the invention are particularly suitable as modulators of the metabotropic glutamate receptor of subtype 1, very particularly as antagonists of this receptor subtype.
  • the compounds according to the invention can be used, on their own or in combination with other pharmaceuticals, for the treatment and/or prevention of neuronal damage or disorders associated with a decompensation of the physiological or with pathophysiological conditions of the glutamatergic system in the central and peripheral nervous system.
  • neuronal damage caused, for example, by ischaemic, thromb- and/or thrombemolic, and haemorrhagic stroke, conditions after direct and indirect injuries in the area of the brain and the skull.
  • cerebral ischaemias after all surgical interventions in the brain or peripheral organs or body parts and conditions of pathogenic or allergic nature accompanying or preceding them, which can lead primarily and/or secondarily to neuronal damage.
  • the compounds according to the invention are also suitable for the therapy of primary and/or secondary pathological conditions of the brain, for example during or after cerebral vasospasms, hypoxia and/or anoxia of previously unmentioned origin, pefinatal asphyxia, autoimmune disorders, metabolic and organ disorders which can be accompanied by damage to the brain, and also damage to the brain as a result of primary brain disorders, for example convulsive conditions and atero- and/or arteriosclerotic changes.
  • neurodegenerative disorders such as, for example, Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and/or chronic viral or bacterial infections and multlinfarct dementia.
  • they can be used as pharmaceuticals for the prevention and/or treatment of dementias of different origin, impaired brain performance owing to old age, memory disturbances, spinal injuries, states of pain, states of anxiety of different origin, medicament-related Parkinson's syndrome, psychoses (such as, for example, schizophrenia), brain oedma, neuronal damage after hypoglycaemia, emesis, nausea, obesity, addiction and withdrawal syndromes, CNS-mediated spasms, sedation and motor disturbances.
  • dementias of different origin impaired brain performance owing to old age, memory disturbances, spinal injuries, states of pain, states of anxiety of different origin, medicament-related Parkinson's syndrome, psychoses (such as, for example, schizophrenia), brain oedma, neuronal damage after hypoglycaemia, emesis, nausea, obesity, addiction and withdrawal syndromes, CNS-mediated spasms, sedation and motor disturbances.
  • the compounds can be used for promoting neuronal regeneration in the post-acute phase of cerebral injuries or chronic disorders of the nervous system.
  • They are preferably employed as pharmaceuticals for the prevention and/or treatment of cerebral ischaemias, craniocerebral trauma, states of pain or CNS-mediated spasms (such as, for example, epilepsy).
  • the modulation of substances at the metabotropic glutamate receptor can be examined using primary cultures of granular cells from the cerebellum. Electrophysiological measurements on these cell cultures in the “cell attached” mode show that L-type Ca 2+ -channels in this preparation are activated by mGluR1-glutamate receptors (J. Neurosci. 1995, 15, 135), whereas they are blocked by group II receptors (J. Neurosci. 1994, 14, 7067).
  • mGluR1-glutamate receptors J. Neurosci. 1995, 15, 135
  • group II receptors J. Neurosci. 1994, 14, 7067
  • the medium cerebral artery is exposed on one side and the latter and its side branches are irreversibly sealed by means of electrocoagulation.
  • the cerebral infarct is formed.
  • the body temperature of the animal is kept at 37° C.
  • the animals are again released into their cage.
  • the administration of the substance is carried out according to different time schemes and via different administration routes (i.v. i.p.) after occlusion.
  • the infarct size is determined after 7 days. To do this, the brain is removed, worked up histologically and the infarct volume is determined with the aid of a computer-assisted analysis system.
  • the animal's own blood is injected subdurally on one side.
  • An infarct is formed under the haematoma.
  • Substance administration is carried out according to different time schemes and via different administration routes (i.v. i.p.).
  • the determination of the infarct size is carried out as described in the model of permanent focal ischaemia in the rat (MCA-O).
  • the suitability of the compounds according to the invention for treating schizophrenia can be determined by the methods described in Science 1998, 281, 1349-1352 and Eur. J. Pharmacol. 1996, 316, 129-136.
  • the present invention includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, comprise one or more compounds of the general formulae (I), (Ia) and (Ib) or which consist of one or more active compounds of the formulae (I), (Ia) and (Ib) and processes for producing these preparations.
  • the active compounds of the formulae (I), (Ia) and (Ib) should be present in a concentration of from 0.1 to 99.5% by weight, preferably from 0.5 to 95% by weight, of the total mixture.
  • the pharmaceutical preparations may also comprise other pharmaceutically active compounds.
  • compositions can be prepared in a customary manner by known methods, for example with the auxiliary(s) or excipient(s).
  • 2-Oxocyclohexylacetic acid (31.2 g, 200 mmol) is dissolved in 125 ml of 0.2 N aqueous sodium hydroxide solution and, at room temperature, added dropwise to a solution of sodium borohydride (18.9 g, 500 mmol) in 150 ml of 0.2 N aqueous sodium hydroxide solution.
  • the mixture is stirred for 20 h and then cooled to 0° C. and carefully acidified with 6 N HCl.
  • the strongly acidic solution is then heated at 100° C. for 30 min and subsequently stirred overnight.
  • the cold mixture is then extracted with MTBE, and the combined ether phases are washed with 5% strength sodium carbonate solution and sat.
  • Example 2 (fraction 1, diastereomer A) and Example 3 (fraction 2, diastereomer B).
  • Example 2 Analogously to the procedure of Example 1, the title compound is was prepared from 1.2 g (9.5 nmuol) of hexahydro-cyclopenta[b]furan-2-one, 10 ml of 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 1.29 g (9.5 mmol) of allyl bromide in 20 ml of THF. Yield: 1.25 g (79%) of a colourless oil.
  • Example 4 Analogously to the procedure of Example 4, the title compound is prepared from 0.55 g (3.3 mmol) of the compound from Example 3, 4 ml of 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 0.73 g (3.3 mmol) of 2-(bromomethyl)-naphthalcne in 15 ml of THF. Yield: 823 mg (81.2%) of a colourless oil.
  • Example 7 Analogously to the procedure of Example 1, the title compound was prepared from 7.4 g (59.6 mmol) of 3,3a,6,6a-tetrahydro-cyclopenta[b]furan-2-one, 60 ml of a 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 13.2 g (59.7 mmol) of 2-(bromomethyl)-naphthalene in 180 ml of THF. Chromatographic purification is carried out using a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100:4. Yield: 10.6 g (67.3%), pale yellow oil, diastereomeric mixture: 2.5:1 (Example 7). MS (ESI)[m/e]: 287 [M+Na + ]
  • Example 3 Analogously to the procedure of Example 3, the title compound was prepared from 0.79 g (3 mmol) of the compound from Example 7, 3 ml of 1 molar lithium bis(trimethylsilyl)-amide solution in THF and 0.36 g (3 mmol) of allyl bromide in 10 ml of THF. Chromatographic purification was carried out using a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100:4. Yield: 684 mg (74.8%) of a pale yellow oil; Diastereomeric purity: >99% de (HPLC).
  • Example 3 Analogously to the procedure of Example 3, the title compound was prepared from 0.42 g (2.56 mmol) of the compound from Example 12, 2.6 ml of 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 0.57 g (2.56 mmol) of 2-bromomethylnaphthalene in 5 ml of THF. Chromatographic purification was carried out using a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100:4. Yield: 487 mg (62.6%) of a pale yellow oil. Diastereomeric purity: >99% de (HPLC).
  • Example 4 Analogously to the procedure of Example 4, the title compound was prepared from 0.4 g (1.5 mmol) of the compound from Example 15, 1.5 ml of 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 0.22 g (1.8 mmol) of allyl bromide in 10 ml of THF. Yield: 198 mg (43.2%) of a pale yellow oil. Diastereomeric purity: 72% de (HPLC).
  • Example 4 Analogously to the procedure of Example 4, the title compound was prepared from 0.23 g (1.38 mmol) of the compound from Example 16, 1.4 ml of 1 molar lithium bis-(trimethylsilyl)-amide solution in THF and 0.3 g (1.38 mmol) of 2-bromomethylnaphthalene in 5 ml of THF. Yield: 259 mg (61.8%) of a pale yellow oil. Diastereomeric purity: >99% de (HPLC).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
US09/600,430 1998-01-17 1999-01-05 Substituted β,γ-anellated lactones Expired - Fee Related US6433004B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19801647A DE19801647A1 (de) 1998-01-17 1998-01-17 Substituierte beta,gamma-annellierte Lactone
DE19801647 1998-01-17
PCT/EP1999/000022 WO1999036417A1 (fr) 1998-01-17 1999-01-05 β,η-LACTONES SUBSTITUEES

Publications (1)

Publication Number Publication Date
US6433004B1 true US6433004B1 (en) 2002-08-13

Family

ID=7854913

Family Applications (1)

Application Number Title Priority Date Filing Date
US09/600,430 Expired - Fee Related US6433004B1 (en) 1998-01-17 1999-01-05 Substituted β,γ-anellated lactones

Country Status (6)

Country Link
US (1) US6433004B1 (fr)
EP (1) EP1047685A1 (fr)
JP (1) JP2002509145A (fr)
AU (1) AU2419899A (fr)
DE (1) DE19801647A1 (fr)
WO (1) WO1999036417A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI415842B (zh) * 2005-12-09 2013-11-21 Chinoin Gyogyszer Es Vegyeszet 新穎方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004501970A (ja) 2000-07-03 2004-01-22 イーベーヴェーエフ　インスティチュート　フュア　ビオテヒノロジ　ウント　ヴィルクシュトフ−フォルシュング　エーファウ ガリエララクトンの利用
TWI375121B (en) * 2004-06-28 2012-10-21 Fujifilm Corp Photosensitive composition and method for forming pattern using the same

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS49110659A (fr) * 1973-03-06 1974-10-22
WO1992010583A1 (fr) 1990-12-12 1992-06-25 Zymogenetics, Inc. Recepteurs de glutamate couples a une proteine g
EP0656345A1 (fr) 1993-12-03 1995-06-07 Université Louis Pasteur Dérivés d'acide aspartique ou ses homologues et leur application en traitement des troubles du système nerveux central
WO1995015941A1 (fr) 1993-12-10 1995-06-15 University Of Bristol Amino-acides substitues par aryle, agents influant sur le snc
WO1995015940A1 (fr) 1993-12-10 1995-06-15 University Of Bristol Alpha-aminoacides alpha quaternaires utilises comme agents influant sur le snc (systeme nerveux central)
EP0658539A1 (fr) 1993-12-03 1995-06-21 Eli Lilly And Company Antagonistes des récepteurs des aminoacides excitatoires
WO1995025110A1 (fr) 1994-03-14 1995-09-21 Novo Nordisk A/S Composes heterocycliques, leur preparation et leur utilisation
WO1996005818A1 (fr) 1994-08-19 1996-02-29 Nps Pharmaceuticals, Inc. Procedes et composes actifs au niveau des recepteurs de glutamate metabotropiques, destines au traitement d'affections et de troubles neurologiques
WO1996007405A1 (fr) 1994-09-08 1996-03-14 Eli Lilly And Company Antagonistes des recepteurs d'acides amines excitateurs
WO1996015099A1 (fr) 1994-11-09 1996-05-23 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation de ces composes
WO1997001790A1 (fr) 1995-06-29 1997-01-16 Bell Communications Research, Inc. Dispositifs a cristaux liquides nematiques en super helice et en helice inversee
WO1997005109A1 (fr) 1995-07-31 1997-02-13 Novo Nordisk A/S Composes heterocycliques, leur preparation et utilisation
WO1997005137A1 (fr) 1995-07-31 1997-02-13 Novo Nordisk A/S Composes heterocycliques, et preparation et utilisation de ces derniers
EP0774461A1 (fr) 1995-11-16 1997-05-21 Eli Lilly And Company Dérivés des aminoacides excitateurs
EP0774454A1 (fr) 1995-11-16 1997-05-21 Eli Lilly And Company Antagonistes des récepteurs d'aminoacides excitateurs
US5688826A (en) 1995-11-16 1997-11-18 Eli Lilly And Company Excitatory amino acid derivatives
US5843988A (en) 1994-10-21 1998-12-01 Suntory Limited Cyclopropachromencarboxylic acid derivatives

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS49110659A (fr) * 1973-03-06 1974-10-22
WO1992010583A1 (fr) 1990-12-12 1992-06-25 Zymogenetics, Inc. Recepteurs de glutamate couples a une proteine g
EP0656345A1 (fr) 1993-12-03 1995-06-07 Université Louis Pasteur Dérivés d'acide aspartique ou ses homologues et leur application en traitement des troubles du système nerveux central
EP0658539A1 (fr) 1993-12-03 1995-06-21 Eli Lilly And Company Antagonistes des récepteurs des aminoacides excitatoires
WO1995015941A1 (fr) 1993-12-10 1995-06-15 University Of Bristol Amino-acides substitues par aryle, agents influant sur le snc
WO1995015940A1 (fr) 1993-12-10 1995-06-15 University Of Bristol Alpha-aminoacides alpha quaternaires utilises comme agents influant sur le snc (systeme nerveux central)
WO1995025110A1 (fr) 1994-03-14 1995-09-21 Novo Nordisk A/S Composes heterocycliques, leur preparation et leur utilisation
WO1996005818A1 (fr) 1994-08-19 1996-02-29 Nps Pharmaceuticals, Inc. Procedes et composes actifs au niveau des recepteurs de glutamate metabotropiques, destines au traitement d'affections et de troubles neurologiques
WO1996007405A1 (fr) 1994-09-08 1996-03-14 Eli Lilly And Company Antagonistes des recepteurs d'acides amines excitateurs
US5843988A (en) 1994-10-21 1998-12-01 Suntory Limited Cyclopropachromencarboxylic acid derivatives
WO1996015099A1 (fr) 1994-11-09 1996-05-23 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation de ces composes
WO1996015100A1 (fr) 1994-11-09 1996-05-23 Novo Nordisk A/S Composes heterocycliques, preparation et utilisation
WO1997001790A1 (fr) 1995-06-29 1997-01-16 Bell Communications Research, Inc. Dispositifs a cristaux liquides nematiques en super helice et en helice inversee
WO1997005109A1 (fr) 1995-07-31 1997-02-13 Novo Nordisk A/S Composes heterocycliques, leur preparation et utilisation
WO1997005137A1 (fr) 1995-07-31 1997-02-13 Novo Nordisk A/S Composes heterocycliques, et preparation et utilisation de ces derniers
EP0774461A1 (fr) 1995-11-16 1997-05-21 Eli Lilly And Company Dérivés des aminoacides excitateurs
EP0774454A1 (fr) 1995-11-16 1997-05-21 Eli Lilly And Company Antagonistes des récepteurs d'aminoacides excitateurs
US5688826A (en) 1995-11-16 1997-11-18 Eli Lilly And Company Excitatory amino acid derivatives

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
Bando, T.; Tanaka, S.; Fugami, K.; Yoshida, Z.; Tamaru, Y.; "Efficient Systhesis of 2-Vinyl-gamma-butyrolactones and 2-Vinyl-gamma-butyrolactams by Paladium-Catalyzed Decarboxylative Carbonylation ", Bull. Chem. Soc. Jpn. 65:97-110 (1992).
Bando, T.; Tanaka, S.; Fugami, K.; Yoshida, Z.; Tamaru, Y.; "Efficient Systhesis of 2-Vinyl-γ-butyrolactones and 2-Vinyl-γ-butyrolactams by Paladium-Catalyzed Decarboxylative Carbonylation ", Bull. Chem. Soc. Jpn. 65:97-110 (1992).
Chavis, P., Nooney, J. M., Bockaert, J., Fagni, L., Feltz, A., and J. L. Bossu, "Facilitatory Coupling between a Glutamate Metabotropic Receptor and Dihydropyridine-Sensitive Calcium Channels in Cultured Cerebellar Granule Cells", J. Neurosci., 15(1): 135-143 (Jan. 1995).
Chavis, P., Shinozaki, H., Bockaert, J., and Fagni, L., "The Metabotropic Glutamate Receptor Types 2/3 Inhibit L-Type Calcium Channels via a Pertussis Toxin-Sensitive G-Protein in Cultured Cerebellar Granule Cells", J. Neurosci., 14(11): 7067-7076 (Nov. 1994).
Conn, J. P., and Pin, J.-P., "Phamacology and Functions of Metabotropic Glutamate Receptors", Annu. Rev. Pharmacol. Toxicol., 37: 205-237 (1997).
Kelly, H. A.; Bolton, R.; Brown, S. A.; Coote, S. J.; Dowle, M.; Dyer, U.; Finch, H.; Golding, D.; Lowdon A.; McLaren, J.; Montana, J. G.; Owen, M. R.; Pegg, N. A.; Ross, B. C.; Thomas, R.; and Walker, D. A., "Synthesis of Tran-Fused [5,5] Bicyclic Lactones / Lactams as Templates for Serine Protease Inhibition", Tetrahedron Letters 39,(38): 6979-6982 (1998).
Smith, A. B.; and Richmond, R. E., "Total Synthesis of the Paniculides ", J. Am. Chem. Soc. 105: 575-585 (1983).

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI415842B (zh) * 2005-12-09 2013-11-21 Chinoin Gyogyszer Es Vegyeszet 新穎方法

Also Published As

Publication number Publication date
EP1047685A1 (fr) 2000-11-02
JP2002509145A (ja) 2002-03-26
WO1999036417A1 (fr) 1999-07-22
DE19801647A1 (de) 1999-07-22
AU2419899A (en) 1999-08-02

Similar Documents

Publication Publication Date Title
TWI832962B (zh) 雜環化合物及其用途
DK2380881T3 (en) NEW BICYCLIC HETEROCYCLIC COMPOUND
JP6347797B2 (ja) 二環式アリールスフィンゴシン１−リン酸類似体
RU2089549C1 (ru) Производные гетероциклилметилхромана в виде смеси изомеров или отдельных изомеров или их соли
JP6262733B2 (ja) イミダゾリン誘導体、その製造法、およびそれらの医薬への適用
BR112020000823A2 (pt) composto, medicamento, métodos para ativar um receptor de orexina tipo 2 e para profilaxia ou tratamento de narcolepsia, e, uso de um composto ou sal.
JP2002523396A (ja) 新規なアリールスルホンアミドアミノ酸エステル類および同族体
WO2013104257A1 (fr) Dérivés polycycliques, leur procédé de préparation et leurs utilisations médicales
JP2002529529A (ja) 興奮性アミノ酸レセプターモジュレーター
CN115003670A (zh) 杂环化合物
WO2014031755A1 (fr) Dérivés de fendiline et leurs procédés d'utilisation
KR20160106684A (ko) 히드록시포름아미드 유도체 및 그의 용도
JP2002512214A (ja) 代謝生成物産生グルタミン酸レセプターアンタゴニストとしてのキュバン誘導体およびそれらの調製プロセス
US6723718B2 (en) Substituted α, β-anellated butyrolactones
IE883248L (en) Benzopyrans and intermediates
JP3162523B2 (ja) ピペリジルメチル−置換クロマン誘導体
EP4508027A1 (fr) Composé hétérocyclique
US6433004B1 (en) Substituted β,γ-anellated lactones
TW201704206A (zh) 環狀化合物
US6060482A (en) Triazaspirodecanone-methylchromans
ES2312399T3 (es) Procedimiento para preparar compuestos de 2,3-dihidrobenzofurano opticamente activos.
US6376539B1 (en) Substituted bicyclic lactones
KR20230118970A (ko) 치환된 시클로헥산카복스아마이드, 이의 제조 방법및 이의 치료적 용도
DE69707793T2 (de) Alkynylaminosäure Derivate und ihre Verwendung als pharmazeutische Verbindungen
HK1162504B (en) Novel bicyclic heterocyclic compound

Legal Events

Date Code Title Description
AS Assignment

Owner name: BAYER AKTIENGESELLSCHAFT, GERMANY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:STOLLE, ANDREAS;ANTONICEK, HORST-PETER;LENSKY, STEPHEN;AND OTHERS;REEL/FRAME:011147/0483;SIGNING DATES FROM 20000605 TO 20000713

FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20100813